WASHINGTON Researchers have closed the Prostate Cancer
Prevention Trial (PCPT) 15 months early after finding that men who took Proscar
(finasteride) had a 25% lower risk of developing the disease, compared with men
given placebo. "This trial proves that prostate cancer, at least in part,
is preventable. It is a huge step forward for cancer research," Peter
Greenwald, MD, DrPH, director of the National Cancer Institute’s Division of
Cancer Prevention, said at a press conference announcing the results.

The study also found that men taking finasteride had a
significantly greater number of high-grade tumors than those in the placebo
arm. This noted, "98% of all cancers diagnosed in the entire PCPT were
localized to the prostate at the time of diagnosis," said principal
investigator Ian M. Thompson, MD, of the University of Texas Health Science
Center in San Antonio.

The 10-year PCPT was scheduled to end in May 2004. However,
the study’s independent data and safety monitoring committee concluded on
Feb. 21, 2003, that the data already collected were sound and unlikely to
change with the addition of more data, and on March 3, it recommended closing
the trial. The committee based its recommendation on findings from 9,060 trial
participants who had developed prostate cancer or completed the study’s
7-year follow-up process.

The Food and Drug Administration initially approved Proscar
in 1992 as a 5-mg/d treatment for benign prostatic hyperplasia (BPH), and later
approved its sale in a 1-mg daily dose, marketed as Propecia, to treat
male-pattern hair loss.

The drug inhibits the steroid 5a-reductase, an enzyme that
converts testosterone to androgen dihydrotestosterone (DHT). Because strong
evidence supports the influence of androgens on the development of prostate
cancer, researchers decided to test finasteride as a possible means of reducing
the disease prevalence.

The PCPT was funded by the NCI, coordinated by the Southwest
Oncology Group (SWOG), and carried out at 219 sites. Researchers originally
considered using mortality as an endpoint for PCPT but found that would require
a 15-year trial involving 50,000 men. "It was just too big a bite,"
said SWOG chair Charles E. Coltman, MD.

Between January 1994 and May 1997, the controlled,
double-blind study enrolled 18,882 men ages 55 or older with normal digital
rectal examinations and PSA levels of 3 ng/mL or lower. The men were randomized
to either 5 mg of finasteride daily or placebo. Participants underwent a yearly
digital rectal exam and PSA test. They also agreed to an end-of-study biopsy
after 7 years if they had not been diagnosed with prostate cancer during the
trial.

Among the 9,060 men included in the data analysis, 803
(18.4%) of the 4,368 randomized to the Proscar group and 1,147 (24.4%) of the
4,692 participants in the placebo arm were diagnosed with prostate cancer, a
relative risk reduction of 24.8% (P < .001). "The reduction in
prostate cancer was noted at 1 year and continued over the 7 years of the
study," Dr. Thompson said.

Prostate cancer was diagnosed due to biopsy for cause in 435
of the finasteride group and 571 of the placebo group. Prostate cancer was
diagnosed as a result of the end-of-study biopsy in 368 of the men taking
finasteride and 576 of those in the placebo group.

The tumors detected by biopsy performed for cause were
clinically similar to those found in clinical practice due to biopsy based on
PSA screening and digital rectal examination. The clinical significance of
cancers found in the end-of-study biopsies is unknown, the researchers said.

High-Grade Tumors

The study’s central pathology laboratory reported that
among the men in the study who developed prostate cancer, those in the
finasteride arm had a larger proportion of tumors with high Gleason scores than
those who received placebo. In the finasteride arm, 280 (37%) of 757 graded
tumors had Gleason scores of 7 to 10, compared with 237 (22.2%) of 1,068 graded
tumors from the placebo group. Thus, tumors with high Gleason scores were found
in 6.4% of the men treated with finasteride vs 5.1% of the placebo group.

"There are several hypotheses about these tumors and
whether they are real or just an artifact," Dr. Ford commented. "Only
time and continued follow-up will tell us whether these tumors behave like
traditional tumors or are, in fact, more like the low-grade tumors." [See
box on page 6.]

Adverse Events

An analysis of adverse events reported by all participants9,423
men receiving finasteride and 9,437 on placebofound sexual side effects were
significantly more common in the treatment arm, and urinary problems were
significantly more common in the control group.

Sexual side effects included reduced volume of ejaculate
(60.4% in the treatment arm vs 47.3% in the placebo group), erectile
dysfunction (67.4% vs 61.5%), loss of libido (65.4% vs 59.6%), and gynecomastia
(4.5% vs 2.8%). One man in each arm developed breast cancer.

Both Dr. Ford and Dr. Thompson noted that the PCPT has
yielded a trove of blood samples, prostate tissue, and tumor specimens that
will provide the basis for further studies related to prostate cancer.

The full PCPT report appears in the July 17, 2003, issue of The New
England Journal of Medicine.

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